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Biomedical subjects

Tomi Järvinen

Publications and source records attributed to Tomi Järvinen.

At least 19 recordsLinked to original sources
PubMed2007

Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac: suppressing the rearrangement pathway in aqueous media.

Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O-->N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.

Administration, Oral↗
PubMed2007

Precipitation complexation method produces cannabidiol/beta-cyclodextrin inclusion complex suitable for sublingual administration of cannabidiol.

In the present study, the precipitation complexation method was used to prepare a complex of cannabidiol (CBD) with beta-CD. The effect of beta-CD-complexation on the sublingual absorption of CBD was studied in rabbits. A solid CBD/beta-CD inclusion complex was prepared by precipitation and the effect of complex formation on the dissolution rate of CBD was studied. The absorption of CBD (a 250 microg/kg dose of CBD in all formulations) after sublingual administration of solid CBD/beta-CD complex and ethanolic CBD solution, and after oral administration of ethanolic CBD solution, was studied in vivo in rabbits. The dissolution rate of solid CBD/beta-CD complex in vitro was significantly (p<0.05) higher than that of plain CBD. The absorption of CBD (AUC0-300 min) decreased in the following order: sublingual ethanolic CBD solution (420+/-120 ngxmin/mL; mean+/-SD; n=4)>sublingual solid CBD/beta-CD complex (270+/-120 ngxmin/mL)>oral ethanolic CBD solution (concentrations in plasma below the quantitation limit). The results demonstrate that sublingual administration of a solid CBD/beta-CD complex enhances the absorption of CBD in rabbits when compared to oral administration of ethanolic CBD. Furthermore, the solid CBD/beta-CD complex may provide an alternative formulation for sublingual administration of CBD.

Absorption↗
PubMed2007

Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis.

As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Administration, Cutaneous↗
PubMed2006

N,N'-Bisbenzylidenebenzene-1,4-diamines and N,N'-Bisbenzylidenenaphthalene-1,4-diamines as Sirtuin Type 2 (SIRT2) Inhibitors.

A series of N,N'-bisbenzylidenebenzene-1,4-diamine and N,N'-bisbenzylidenenaphthalene-1,4-diamine derivatives were synthesized as inhibitors for human sirtuin type 2 (SIRT2). The design of the new compounds was based on two earlier reported hits from molecular modeling and virtual screening. The most potent compound was N,N'-bis(2-hydroxybenzylidene)benzene-1,4-diamine, which was equipotent with the most potent hit compound and well-known SIRT2 inhibitor sirtinol.

Acetylation↗
PubMed2006

Effects of hempseed and flaxseed oils on the profile of serum lipids, serum total and lipoprotein lipid concentrations and haemostatic factors.

BACKGROUND: Both hempseed oil (HO) and flaxseed oil (FO) contain high amounts of essential fatty acids (FAs); i.e. linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3), but almost in opposite ratios. An excessive intake of one essential FA over the other may interfere with the metabolism of the other while the metabolisms of LA and ALA compete for the same enzymes. It is not known whether there is a difference between n-3 and n-6 FA of plant origin in the effects on serum lipid profile. AIM OF THE STUDY: To compare the effects of HO and FO on the profile of serum lipids and fasting concentrations of serum total and lipoprotein lipids, plasma glucose and insulin, and haemostatic factors in healthy humans. METHODS: Fourteen healthy volunteers participated in the study. A randomised, double-blind crossover design was used. The volunteers consumed HO and FO (30 ml/day) for 4 weeks each. The periods were separated by a 4-week washout period. RESULTS: The HO period resulted in higher proportions of both LA and gamma-linolenic acid in serum cholesteryl esters (CE) and triglycerides (TG) as compared with the FO period (P < 0.001), whereas the FO period resulted in a higher proportion of ALA in both serum CE and TG as compared with the HO period (P < 0.001). The proportion of arachidonic acid in CE was lower after the FO period than after the HO period (P < 0.05). The HO period resulted in a lower total-to-HDL cholesterol ratio compared with the FO period (P = 0.065). No significant differences were found between the periods in measured values of fasting serum total or lipoprotein lipids, plasma glucose, insulin or hemostatic factors. CONCLUSIONS: The effects of HO and FO on the profile of serum lipids differed significantly, with only minor effects on concentrations of fasting serum total or lipoprotein lipids, and no significant changes in concentrations of plasma glucose or insulin or in haemostatic factors.

Adult↗
PubMed2006

An introduction of a pyridine group into the structure of prolyl oligopeptidase inhibitors.

A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-l-prolyl group at the P2 position, good lipophilicity can be achieved.

Enzyme Inhibitors↗
PubMed2006

Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system.

The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitors was performed by utilizing a comparative model of the human MGL enzyme. All hit molecules were tested for their potential MGL inhibitory activity, but no compounds were found capable of inhibiting MGL-like enzymatic activity in rat cerebellar membranes. However, these compounds were also tested for their potential FAAH inhibitory activity and five compounds (2-6) inhibiting FAAH were found with IC50 values between 4 and 44 microM. In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM. Additionally, compound 7 inhibited MGL-like enzymatic activity with an IC50 value of 31 microM.

Amidohydrolases↗
PubMed2006

Synthesis, cannabinoid receptor activity, and enzymatic stability of reversed amide derivatives of arachidonoyl ethanolamide.

Retroanandamide (2f) and its 10 analogues (1a-e, 2a-e) were synthesized and evaluated for the cannabinoid receptor activation by a [35S]GTPgammaS binding assay using rat cerebellar membranes, and Chinese hamster ovary cell membranes expressing human CB2 receptors. The primary goal of the study was to develop cannabinoid receptor agonists having improved enzymatic stability compared to endogenous N-arachidonoyl ethanolamide (AEA). Furthermore, by reversing the amide bond of AEA, the formation of arachidonic acid would be prevented. Finally, an effect of the carbonyl carbon position on the cannabinoid receptor activity was explored by synthesizing retroanandamide analogues having different chain lengths (1a-e, C19; 2a-f, C20). All the synthesized compounds, except 2c, behaved as partial agonists for the both cannabinoid receptors. In rat brain homogenate, the reversed amides possessed significantly higher stability against FAAH induced degradation than AEA. Therefore, the reversed amide analogues of AEA may serve as enzymatically stable structural basis for the drug design based on the endogenous cannabinoids.

Amides↗
PubMed2006

Synthesis and SAR studies of 2-oxoquinoline derivatives as CB2 receptor inverse agonists.

The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid N-benzo[1,3]dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and effective CB2 receptor inverse agonists. A series of aromatic amides of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 6 was synthesized, and the CB2 receptor activities of the compounds were determined by a [35S]GTPgammaS-binding assay using membranes of CHO cells stably transfected with the human CB2 receptor. As a result, all the compounds were defined as full CB2 receptor inverse agonists, and additionally, except for two 3,4-dihydroxyphenylalkylamides, they were found to be equally potent as SR144528.

Animals↗
PubMed2006

Novel water-soluble quaternary piperazine derivatives of chitosan: synthesis and characterization.

Novel synthesis methods for the preparation of quaternary piperazine derivatives of chitosan were developed. Quaternary ammonium moiety can be selectively inserted into either one or both of the piperazine nitrogens, yielding structurally uniform chitosan derivative structures. Water-soluble end products were thoroughly characterized with FT-IR, 1H NMR, 13C NMR and 2D 1H-13C HSQC NMR. The molecular weights of the end products were determined by GPC with triple detection.

Biocompatible Materials↗
PubMed2006

Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure.

Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.

Alanine Transaminase↗
PubMed2006

Alpha-methylated derivatives of 2-arachidonoyl glycerol: synthesis, CB1 receptor activity, and enzymatic stability.

Alpha-methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPgammaS binding assay, and the enzymatic stability of alpha-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the alpha-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.

Animals↗
PubMed2006

3D-QSAR studies on cannabinoid CB1 receptor agonists: G-protein activation as biological data.

G-protein activation via the CB1 receptor was determined for a group of various CB1 ligands and utilized as biological activity data in subsequent CoMFA and CoMSIA studies. Both manual techniques and automated docking at CB1 receptor models were used to obtain a common alignment of endocannabinoid and classical cannabinoid derivatives. In the final alignment models, the endocannabinoid headgroup occupies a unique region distinct from the classical cannabinoid structures, supporting the hypothesis that these structurally diverse molecules overlap only partially within the receptor binding site. Both CoMFA and CoMSIA produce statistically significant models based on the manual alignment and a docking alignment at one receptor conformer. Leave-half-out cross-validation and progressive scrambling were successfully used in assessing the predictivity of the QSAR models.

Animals↗
PubMed2006

Synthesis and CB1 receptor activities of dimethylheptyl derivatives of 2-arachidonoyl glycerol (2-AG) and 2-arachidonyl glyceryl ether (2-AGE).

Results from a factor analysis and activity studies of commercially available endocannabinoid-type compounds set the starting point for the current study where dimethylheptyl (DMH) analogues of two endocannabinoids, 2-arachidonoyl glycerol (2-AG) and 2-arachidonyl glyceryl ether (2-AGE), were synthesized and their ability to activate the CB1 receptors was determined by the [35S]GTPgammaS binding assay using rat cerebellar membranes. The main goal of the study was to examine how the DMH end tail affects the activity properties of 2-AG (1) and its stable ether (2) and urea analogues (5). The importance of the chain length was also explored by synthesizing 2-AG and 2-AGE derivatives (3 and 4) possessing the chain length C21 instead of C22. Replacement of the pentyl end chain with the DMH resulted in distinct potency decrease as compared to the reference compounds. The modification did not have such a strong impact on the efficacy values. In fact, the efficacy of the derivatives of 2-AGE (2 and 4) was comparable or even improved. Introducing a more stable and hydrophilic urea bond led to a dramatic decrease in biological activity.

Arachidonic Acids↗
PubMed2006

Preparation of budesonide/gamma-cyclodextrin complexes in supercritical fluids with a novel SEDS method.

The aim was to investigate if solid drug/cyclodextrin complexes could be produced in a single-step process with a solution enhanced dispersion by supercritical fluids (SEDS) method. Budesonide and gamma-cyclodextrin (CD) solutions (50% or 99.5% ethanol) were pumped from the same (conventional method) or separate (modified method) containers together with supercritical carbon dioxide through a coaxial nozzle into a particle formation chamber. The pressure was maintained at 100, 150 or 200 bar with a temperature of 40, 60 or 80 degrees C. SEDS-processed powders were characterised with HPLC, DSC and XRPD for budesonide content, complexation and crystallinity. The budesonide dissolution rate was determined in 1% gamma-CD aqueous solution. Solid, white budesonide/gamma-CD complex particles were formed using the conventional and modified SEDS processes. The complexation efficiency was dependent on the processing conditions. For example, with the conventional method (100 bar, 60 degrees C) the yield of the powder was 65+/-12% with 0.14+/-0.02 mg budesonide/mg powder, corresponding to 1:2 drug:CD molar ratio. The dissolution rate of this complexed budesonide (93+/-2% after 15 min) was markedly higher compared to unprocessed micronised budesonide (41+/-10%) and SEDS-processed budesonide without CD (61+/-3%). As a conclusion, SEDS is a novel method to produce solid drug/CD complexes in a single-step process.

Budesonide↗
PubMed2006

URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain.

Previous studies indicate that in brain tissue the endocannabinoid 2-AG is inactivated by monoglyceride lipase (MGL)-catalyzed hydrolysis, and a recent report has indicated that MGL activity could be specifically inhibited by URB754 . In the present study, URB754 failed to inhibit 2-AG hydrolysis in rat brain preparations. In addition, brain cryosections were employed to assess whether URB754 could facilitate the detection of 2-AG-stimulated G protein activity. Nevertheless, whereas pretreatment with PMSF readily allowed detection of 2-AG-stimulated G protein activity, URB754 was ineffective. In contrast to previous claims, brain FAAH activity was also resistant to URB754. Thus, in our hands URB754 was not able to block the endocannabinoid-hydrolyzing enzymes and cannot serve as a lead structure for future development of MGL-specific inhibitors.

Aniline Compounds↗
PubMed2006

Synthesis and in vitro evaluation of novel 2-oxo-1,2-dihydroquinoline CB2 receptor inverse agonists.

Aliphatic amides of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 6 were synthesized and evaluated for their CB2 and CB1 receptor activities by a [35S]GTPgammaS membrane-binding assay. Compounds 7-18 produced CB2 inverse agonist activities with a variety of potencies (IC50: 1 nm-1 microm). By contrast, no considerable antagonism of CB1 receptor was observed by 1-10 microm concentrations indicating that synthesized compounds were CB2 receptor selective.

Animals↗